Shima Kanko Hotel, Mie-ken Japan, June 23-24, 1989
The meeting was called to order by Dr. Fuminori Sakai at 9 a.m. He welcomed the members of the Joint Steering Committee of the 16th US-Japan Cooperative Cancer Research Program and introduced the Japanese participants. He regretted that Dr. Yuichi Yamamura was not able to attend the meeting and hoped for a quick recovery from his illness. He announced that Dr. Takashi Sugimura would chair this session.
Dr. Richard Adamson expressed his delight in participating in a well-organized and nicely accommodated meeting by the JSPS in the beautiful country of Kashikojima. He introduced the members of the U.S. delegation, including the new Associate Director for International Affairs, Dr. Federico Welsch. He noted regrets that Dr. Richard Hodes could not be present at this time. Dr. Sugimura introduced Dr. Kunio Aoki, Dr. Toshiyuki Hamaoka, and Dr. Shozo Takayama. He encouraged active discussions for the important topics that had been presented in the workshops and seminars sponsored by the program. Mr. Tatsuo Kishi of the JSPS announced the time schedule of the meeting.
It was officially announced that both NCI and JSPS have agreed to extend the Agreement for its fourth five-year-term beginning April 1, 1989.
Dr. Adamson was first to report on the progress in the Etiology Program Area. Although the seminar "Cytochrome P-450 and Carcinogenesis" belongs to the Biology and Diagnosis Program Area, Dr. Adamson reported it because of the absence of Dr. Hodes and the notable relevancy of the subject with cancer etiology. The seminar was organized by Dr. Harry Gelboin and Dr. Yoshiaki Fuji-Kuriyama. He defined the importance of the cytochrome P-450 enzymes for their crucial role in the activation and detoxification of the environmental carcinogens. The recent remarkable progresses in structural clarification of numerous subgroups, the molecular biology and genetics in relation to carcinogenesis, and to the role in human cancer susceptibility were major topics of discussion. The P-450 is a late limiting factor for the susceptibility of carcinogens. A number of factors which may change the level of P-450 induction were discussed. The difference in P-450 enzymes and other factors among different animal species may contribute to the different susceptibility of the animals against the carcinogens.
Dr. Sugimura mentioned that the cytochrome P-450 was originally discovered by Dr. Ryo Sato of the Osaka University in Japan. The extensive studies which were carried out by scientists in Japan and the U.S. confirmed that the P450 enzymes play crucial roles for chemical carcinogenesis. Therefore, it is a particularly unique and important opportunity to have a meeting jointly attended by the scientists who have contributed to the significant progress made in this field.
The seminar on "Molecular Mechanisms of Viral Carcinogenesis" was organized by Dr. Mitsuaki Yoshida and Dr. Peter Howley and was held in Hawaii. A general review of the molecular biology of human leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) was presented by Dr. Yoshida. Transacting regulators of these viruses were discussed extensively. Also discussed were a new in vitro infection system with infant primary culture cells obtained from human embryo liver, transcriptional factors involved in the regulation of polyoma virus enhancer, transgenic mice with the putative oncogenes from Epstein-Barr virus, adenovirus, and bovine papilloma virus genome contributing for cell growth, immortalization, and transformation under different experimental conditions were discussed.
Dr. Sugimura pointed out that there was a trend in viral oncology to merge with field of biochemical carcinogenesis. For example, unphosphorylated, but not phosphorylated forms, of the retinoblastoma antioncogene (Rb) protein interacts with various viral proteins, such as AdE1A, SV 40 T antigen, middle T antigen of polyoma virus, E6 and E7 of human papilloma virus. Mutated Rb protein remains unbound. These data suggest that unphosphorylated Rb protein is the active form in growth suppression, and the phosphorylated and mutated Rb protein switches off the growth arrest.
Transgenic mice carrying the bovine papilloma virus genome showing fibromatosis was also presented in this seminar. The recent studies developed in the U.S. and presented in the seminar were very stimulating for Japanese scientists who also made significant contribution to the concurrent exchange of scientific information. Dr. Adamson pointed out that human retroviruses of HTLVs and HIV are becoming increasingly important because recent studies reported that coinfection and transactivation result in additional pathogenic causes. Exogenous viral gene products interacting with internal regulatory proteins causing phenotypic changes of the host are an entirely new concept of carcinogenesis emerging from recent studies. Further studies are needed to elucidate the mechanisms of the pathological progression. All participants agreed that the second seminar organized by the same scientists on this topic within the last three years was exceptionally successful and valuable in updating the scientific information.
The seminar on "Multiple Primary Cancers" was organized by Dr. Curtis Harris and Dr. Shaw Watanabe and was held in Hawaii. Hereditary cancer has been the focus of molecular epidemiology, but multiple primary cancers (MPC) also provide good research opportunities, because the occurrence of two or more cancers in a particular person is considered to be a result of interaction between genetic susceptibility and environmental carcinogenesis. Treatments of cancer patients may cause MPC. The current status of MPC was summarized focusing on the epidemiology and molecular genetics of childhood cancers, Iung cancer, GI tract cancer, and other cancers. The loss, deletion, or inactivation of a tumor suppressor gene or antioncogene has been recognized in several types of sporadic cancersas well as MPC. The MPC study would also provide crucial information for chemoprevention and intervention of secondary problems caused by cancer treatment.
Dr. Michael Friedman commented that the studies of the molecular mechanism of cancer would contribute to a new design of treatment such as immuno-preserve and antioncogene therapy and combined chemotherapy, for example. Dr. Miller mentioned that one genetic defect commonly found in one type of cancer is also seen in other types of tumors. Retinoblastomas with different chromosomal changes were also observed. The genetic defect of an original tumor may be the site of defect for the secondary tumor as well.
The seminar on "Fundamental and Clinical Aspects of Pancreatic Cancer" was organized by Dr. Dante Scarpelli and Dr. Yoichi Konishi and held in Hawaii. Current studies on experimental pancreatic cancer, early diagnosis and treatment of human pancreatic carcinoma were presented and discussed. Carcinogenesis and its modulation by chemicals and hormonal factors, transgenic mouse models of acinar cell cancer, tumor markers, and various therapeutic approaches to pancreatic cancer were discussed. Dr. Sugimura mentioned that Dr. MacDonald reported an experimental pancreatic cancer produced in transgenic mice by insertion of a fusion gene consisting of the promoter region of rat trypsin gene linked to the SV40 T antigen structural gene. This is a unique experimental approach designed to elucidate the genetic and molecular mechanism of malignancy, and such an experimental approach would have never come to a scientist's mind several years ago. Participation of clinical doctors and basic researchers for the discussion on a wide range of problems was particularly appreciated by all participants. Dr. Sugano mentioned that most of pancreatic cancers in humans are ductal cell origin, while the majority of the experimental pancreatic cancers produced in animals are mostly of acinar cell origin. Apparent involvement of hormones in human pancreatic cancer was a subject all agreed needed to be studied further.
The seminar on "Marine Natural Products and Cancer" was organized by Dr. Richard Adamson. Dr. Bruce Chabner, and Dr. Hirota Fujiki and was held in Hawaii. The seminar was devoted to discussing drug development for cancer and AIDS, tumor promoters with novel mechanisms of action, and inhibition of tumor promotion as an approach to cancer chemoprevention. Several observers from both nations attended and participated in the seminar, along with many observers from the University of Hawaii and the Cancer Research Center of Hawaii. The seminar began with an overview of the new drug development efforts adopted by the National Cancer Institute. The NCI has initiated a drug screening system based on panels of specific tumor types. Okadaic acid which was found in marine products has provided a new understanding of tumor promotion. Bryostatins in marine bryozoans were discussed with its antitumor, antipromoting, immunomodulation and protein kinase C activating activities. Sarcophytols and agents from cyanobacteria (blue-green algae) were discussed with promising antitumor, as well as anti-AIDS, activities. The seminar was a multidisciplinary discussion and exchange of scientific information among scientists from different fields. During the seminar, it was apparent that the collaboration between U.S. and Japanese scientists will bring rapid advancement in this field. Dr. Sugimura mentioned that the receptors of okadaic acid are a protein phosphatase causing hyperphosphorylation in the cell. Marine natural products, such as okadaic acid, have provided a new understanding of tumor promotion.
Dr. Hamaoka initiated the discussion of the activities in the Biology and Diagnosis Program Area. The seminar on "Activation of Antitumor Effector Mechanisms by Lymphokines and Biological Response Modifiers" was organized by Dr. Hodes and Dr. Hamaoka, and was held in Hawaii. The seminar focused on the mechanisms underlying the host immune response, and the manner in which biologic response modifiers can influence the host antitumor response. The first session on hematopoiesis and lymphoid differentiation covered basic immunology problems including the lymphocyte differentiation, hematopoiesis, characteristic T cell receptor repertoires and!
!!-expressing T cells. The second session dealt with the cellular effector mechanisms which are active in the host response to tumors. The LAK cell generation and its characterization were discussed extensively. The third session on the effect of lymphokines on effector cell function dealt with an adult T cell leukemia-derived factor, and clinical application of IL2. The fourth session for preclinical IL1, anti-CD3 + antihuman tumor antibody conjugates. Unique antigens expressed on tumor cells, which are important in host resistance to tumors, were also discussed. The seminar was marked by extremely active discussion involving clinicians and basic researchers. The second seminar on "Oncogene, Growth Factors, and Receptors" was organized by Dr. Tadamitsu Kishimoto and Dr. Stanley Korsmeyer. The meeting was held in Sapporo, Japan. The first session on DNA binding proteins and regulation of gene expression dealt with two interferon regulatory factors involved in the differential regulation of the beta interferon locus. The second session related to growth factors and receptors. Structural characterization of IL6 and human IL2 receptor subunits were discussed. The third session dealt with T cell receptors. The gamma-delta T cell receptors in humans and mice were discussed. The following session for signal transduction and protein kinase was devoted to discussions on the differential regulation of the LCK gene that encodes the lymphocyte-specific tyrosine kinase. In-depth discussion of the structure, expression and function of the protein kinase C family highlighted the session. Four distinct types of PKCs encoded by three distinct genes were presented. Three additional members of a PKC-related family were introduced. The last session dealt with transgenic mice and oncogenes. A transgene which resulted in a polyclonal expansion of early IgM/IgD follicular center B cells which extended survival in culture was discussed. Transgenic mice with a SV40 promoter and immunoglobulin enhancer in an expression construct containing various oncogenes were produced. These mice demonstrated various abnormalities including tumor formation. A discussion on the factor that affects the tumor phenotype in EÉ -myc transgenic mice concluded the session. It was a very provocative and informative seminar. The current status of the LAK cell treatments and further explanation of the!
!!T cell were provided by Dr. Hamaoka, who responded to questions. Dr. Michael Friedman initiated the report of the Treatment Program Area by giving a general comment on the activities. Four major areas were discussed in the seminar on "Progress in Treatment of Hematologic Tumors: Strategy to Cure." The first discussion was the cell control, particularly with hematopoietic stimulating factors, GCSF and MCSF; second, cellular hematology associated with drug treatment, such as Ara-C; third was the dose intensity, and its related special interest in bone marrow transplantation; fourth was the practical consideration for therapeutic approach against cancer. Dr. Makoto Ogawa described their new approach to overcome treatments of malignant tumors and leukemias that have reached a plateau level. Bone marrow transplantation is a promising new application of treatment and is becoming common in both countries. Dr. Haruo Sugano asked what the clinical application was of the GCSF and MCSF in treatment in both countries. Dr. Friedman responded by saying that a large-scale clinical investigation is in progress in the U.S. Dr. Ogawa mentioned that clinical application of the GCSF in Japan is limited because of the short supply. Erythropoietin is not used for cancer patients with kidney failure.
The seminar on "New Drugs under Development" dealt with new synthetic compounds and natural products. The Japanese scientists presented numerous analogues that are promising for clinical trial and application. The discussion was highly valuable for the exchange of new information, some prior to publication, and to provide a useful bridge for the design of the next generation of drugs. Dr. Ogawa mentioned that the general trend in U.S. academic institutions and industries is increasing interest in new drug development with novel structure, while the Japanese industries are more interested in synthesizing analogues of known compounds for improvements. Many new useful compounds have been developed under a collaborative basis, some of which had been abandoned previously because of the toxicity but revised by chemical modifications.
The seminar on "Innovative Therapy for Poor Prognosis Breast and Gastrointestinal Cancers" was organized to discuss problems of advanced breast cancers and GI cancers that have different treatment approaches from their early stage. Several new studies using adjuvant chemotherapy, antiestrogen sequences, and related oncogene products showed improved response and improved survival. Many of the issues are vital to the clinical programs with a wider application.
Dr. Robert Miller began the session with a report on two seminars held under the Interdisciplinary Program Area. The seminar on "Biostatistics in Cancer Research" was held in Japan because of a large audience, which were expected, and a satellite meeting held in Hiroshima. The meeting was organized by Dr. Robert Miller, Dr. Kunio Aoki, Dr. David Hoel, and Dr. Takashi Yanagawa.
Dr. Aoki mentioned that this was the third meeting held to discuss the biostatistics under the US-Japan Cancer Program. The gap between the epidemiology and biostatistics is becoming narrower each time both sides convene. The main focus of the meeting was the methodology for data collection and management, particularly with the introduction of computer technology. Large-scale cohort studies, data from clinical investigation, and screening data of cervical cancers in Japan were discussed. Mathematical models developed in the U.S. were presented. The measurement errors, resulted from consequences of misspecification, mismeasurement and other components, were discussed. Practical methods for the measurement of statistical inference in cancer risk were also introduced. In general, the U.S. participants specializing in biostatistics were extremely informative to their Japanese counterparts. There is still a significant gap existing between statisticians and epidemiologists, particularly in Japan. However, the seminar provided a great opportunity for these major components to be coordinated.
Dr. Adamson asked about the incidence of HTLV-1 seropositivity which was observed by the general screening. Dr. Sugano responded that the incidence is significantly higher in the endemic areas of southern Japan than in other areas. The transmission is mostly through mother's milk. Intervention studies are in Progress in Japan.
The seminar on "Cancer Registries" was held in conjunction with the annual meeting of the American Association of Central Cancer Registries (AACCR) in Chicago. It was an extraordinary opportunity to bring together the specialists in registries from the two countries and compare the type-specific cancers.
Dr. Aoki, who attended both meetings, reported on this seminar. The U.S. side reported on the present status of cancer registry, data management, and fabrication of the database of the cancer registry. The Japanese side reported on the data analysis, risk assessment, and their cancer control programs. It was observed that the interests of U.S. and Japanese sides are markedly different. Japanese registry groups are active in the development of cancer registry data. Case control studies, hospital based cancer registry, and evaluations of the data were main topics of the Japanese presentations. Cancer registry systems and the SEER program commonly used in the U.S. are different from the ones used in Japan. From this point of view, organization of a facility for cross-national comparison of cancer registry data was proposed and discussed by the participants of both sides. Continuous binational exchange of cancer registry data, codevelopment of modality, migrant studies, registry for latent cancer cases, therapeutic modes, survival data, early detections were recommended to be included in the proposed program.
Dr. Miller mentioned that the joint meeting was particularly beneficial for both sides in terms of learning the system of the other side and establishing new exchanges. Dr. Sugimura added that the meeting was successful in terms of scientific merit received by the large number of participants. However, on the other hand, the original idea of the program was to support small meetings to encourage discussion, rather than numerous presentations. Dr. Miller and Dr. Aoki explained that the two meetings were organized separately but some participants were given the option to attend both meetings. All agreed to keep the program flexible enough to avoid intrusion of excessive bureaucracy.
There were four exchange scientists in the Etiology Program Area. Two compounds were exchanged for collaborative studies between the NCI and the National Cancer Center in Japan. Dr. K. Fujinaga visited Dr. M. Greern, St. Louis University, to study the mechanism of viral carcinogenesis. Dr. Y. Yamazoe visited the laboratories of Dr. P. Guzelian, Dr. F. Gonzales, and Dr. F. Kadlubar for the study of P-450 enzyme. Dr. H. Esumi visited Dr. C. Harris, Dr. B. Weinstein, and Dr. R. Sager for research on environmental carcinogenesis. Dr. Y. Hattori visited Dr. S. Aaronson and Dr. I. Robinson, and discussed growth factors and their corresponding receptors for their role in cell proliferation.
There were three exchange scientists in the Biology and Diagnosis Program Area. Dr. T. Ogura visited Dr. I. Fidler of the M.D. Anderson Cancer Center, and met several scientists at the Harvard Medical School. Current information on immunotherapy with cytokines and related BRM in lung cancer was exchanged. Dr. T. Uede visited Dr. S. Burakoff and Dr. A Houghton to discuss the role of integrin family molecules in T cell activation. Dr. Y. Higashi visited Dr. H. Gelboin to discuss the P-450 enzyme family with their genetic backgrounds.
There were three exchange scientists in the Treatment Program Area. Dr. K. Tamura visited Dr. T. Ohnuma, Dr. E. Henderson, and Dr. Storb to discuss recent advances in cancer chemotherapy and bone marrow transplantation. Dr. S. Asano visited Dr. G. Spitzer, Dr. N. Ihle, Dr. K. Antman and Dr. K. Blume to discuss the recent advances of autologous bone marrow transplantation for cancer treatment. Dr. K. Ezaki visited Dr. J. Gutterman for discussions on the effective way of using BRM for cancer treatment.
There were three exchange scientists in the Interdisciplinary Program Area. Dr. Y. Tsunematsu visited Dr. L. Strong and Dr. A. Meadow to learn methods of genetic cancer epidemiology in the U.S. Dr. K. Yanagihara visited Dr. R. Bassin to discuss differential sensitivity of revertants to transformation by oncogenes. Dr. S. Tsuiki visited Dr. J. Larner of the University of Virginia School of Medicine and a few other institutions to discuss protein phosphatases and protein phosphorylation associated with carcinogenesis.